KR102098977B1 - Heteroaromatic methyl cyclic amine derivative - Google Patents

Abstract

The heteroaromatic ring methyl cyclic amine derivative represented by the following formula (IA), or a pharmaceutically acceptable salt thereof, is a sleep disorder based on orexin (OX) receptor antagonism, depression, anxiety disorder, panic disorder, ataxia, drug dependence , Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, high blood pressure, etc.

Description

Heteroaromatic methyl cyclic amine derivative {HETEROAROMATIC METHYL CYCLIC AMINE DERIVATIVE}

The present invention is a compound having an orexin (OX) receptor antagonist action and a pharmaceutically acceptable salt thereof, and sleep disorders, depression, anxiety disorder, panic disorder, ataxia (mania), drug dependence, containing them as an active ingredient, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, etc.

Orexin is a neuropeptide spliced from preproorexin specifically expressed in the hypothalamic lateral region. So far, OX-A composed of 33 amino acids and OX-B composed of 28 amino acids have been identified, and all of them are deeply involved in the regulation of sleep and wake patterns and the regulation of eating.

OX-A and OX-B both act on the OX receptor. The OX receptor has so far been cloned into two subtypes of the OX1 and OX2 receptors, and it is known that both are membrane transmembrane G protein conjugate receptors that are mainly expressed in the brain. The OX1 receptor is specifically conjugated with Gq in the G protein subclass, while the OX2 receptor is conjugated to Gq and Gi / o (see Non-Patent Document 1 and Non-Patent Document 2).

Tissue distribution differs depending on the subtype of the OX receptor, and the OX1 receptor is expressed at high density in the pelvic nucleus, which is the nucleus of the noradrenaline-operating nerve, and the OX2 receptor is the nucleus of the histamine nerve, the nodular papillary nucleus (non-patent document) 3, non-patent document 4 and non-patent document 5). Expression of both the OX1 receptor and the OX2 receptor is seen in the ventral nucleus, which is the progenitor nucleus of the serotonin nerve, or the dominant nucleus of the dopamine nerve (see Non-Patent Document 3). Orexin nerves project to the brain stem and hypothalamic monoamine nervous system, excitatory effects on their nerves, and the expression of OX2 receptors is also seen in the acetylcholine nerves of the brain stems involved in REM sleep control. It also has an effect on activity (see Non-Patent Document 3 and Non-Patent Document 4).

Recently, attention has been paid to the relationship between OX1 and OX2 receptors to regulate sleep and wakefulness, and the usefulness of compounds having OX receptor antagonism has been studied. When OX-A is administered into the ventricle of a rat, it promotes spontaneous momentum (see non-patent document 6 and non-patent document 7), promotes homology (see non-patent document 7), and prolongs awakening time (non-patent document 6 See). The shortening action of REM sleep time by administration of OX-A is completely antagonized by pretreatment of the OX receptor antagonist (see Non-Patent Document 8). In addition, by administration of substances that antagonize the OX1 and OX2 receptors that can be administered orally to the same extent, a decrease in exercise volume, a reduction in elevation latency, and an increase in non-REM sleep and REM sleep have been reported (Non-Patent Document 9 and See Non-Patent Document 10).

As an OX receptor antagonist compound, a heteroaromatic ring derivative is disclosed in Patent Document 1, but there is no disclosure regarding a compound having a heteroaromatic ring methyl cyclic amine skeleton described herein. Further, as the OX receptor antagonist compound, for example, a compound having various structures described in Non-Patent Document 11 is generally known, but there is no disclosure regarding a compound having a heteroaromatic ring methyl cyclic amine skeleton described herein.

WO2003 / 002559 publication

Zhu Y et al., J. Pharmacol. Sci., 92, 259-266, 2003. Zeitzer JM et al., Trends Pharmacol. Sci., 27, 368-374, 2006. Marcus JN et al., J. Comp. Neurol, 435, 6-25, 2001. Trivedi JP et al., FEBS Lett, 438, 71-75, 1998. Yamanaka A et al., Biochem. Biophys. Res. Commun., 290, 1237-1245, 2002. Hagan JJ et al., Proc. Natl. Acad. Sci. USA, 96, 10911-10916, 1999. Nakamura T et al., Brain Res., 873, 181-187, 2000. Smith MI et al., Neurosci. Lett., 341, 256-258, 2003. Brisbare-Roch C et al., Nat. Med., 13, 150-155, 2007. Cox CD et al., J. Med. Chem., 53, 5320-5332, 2010. John G et al., ChemMed Chem., 5, 1197-1214, 2010.

The object of the present invention is to discover new compounds having OX receptor antagonism, sleep disorders, depression, anxiety disorders, panic disorders, ataxia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine , Pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, and the like to provide treatment or prevention of diseases. More specifically, it is to provide a novel compound exhibiting excellent pharmacokinetics and safety along with excellent OX receptor antagonism.

The present inventors have studied the novel skeletal compound having an antagonistic action against the orexin receptor, and found that the heteroaromatic methyl cyclic amine derivative of any kind represented by the following chemical formula has excellent OX receptor antagonism. , The present invention was completed.

Hereinafter, the present invention will be described in detail. The form of the present invention (hereinafter referred to as "the compound of the present invention") is shown below.

(1) A compound represented by the following formula (IA), or a pharmaceutically acceptable salt thereof.

(In the formula,

X ¹ and X ² represent the same or different nitrogen atom or formula CH,

Y represents the structure of any one of the following formula group (a),

n represents 1 or 2,

R ¹ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group,

R ² represents a triazolyl group, pyridyl group or pyrimidinyl group,

R ³ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group (wherein said C _{1 -6} alkyl group may be substituted with 1 to 3 halogen atoms),

R ⁴ represents a hydrogen atom or a C _{1 -6} alkyl group)

(2) In the formula (IA),

R ² is a triazolyl group or pyrimidinyl group,

The compound according to (1), wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof.

(3) In the formula (IA),

The compound according to (1) or (2), wherein n is 2, or a pharmaceutically acceptable salt thereof.

(4) A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof.

(In the formula,

X ¹ and X ² represent the same or different nitrogen atom or formula CH,

Y ¹ and Y ² are nitrogen atoms on one side and CH on the other side,

n represents 1 or 2,

R ¹ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group,

R ² represents a triazolyl group, pyridyl group or pyrimidinyl group,

R ³ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group (wherein said C _{1 -6} alkyl group may be substituted with 1 to 3 halogen atoms),

R ⁴ represents a hydrogen atom or a C _{1 -6} alkyl group)

(5) In the formula (I),

R ² is a triazolyl group or pyrimidinyl group,

The compound according to (4), wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof.

(6) In the formula (I),

The compound according to (4) or (5), wherein n is 2, or a pharmaceutically acceptable salt thereof.

(7) Any one or two or more mixtures selected from the following group of compounds described in (1) above and pharmaceutically acceptable salts thereof.

(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-(2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-(2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[(2S, 5S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[(2S, 5R) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

[(2S, 4R) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazolidine-3 -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[(2S, 4S) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(±) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,

(±)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Fluoro-2- (pyrimidin-2-yl) phenyl] methanone,

(±)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (Pyrimidin-2-yl) phenyl] methanone,

(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,

(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( 2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,

(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( Pyrimidin-2-yl) pyridin-2-yl] methanone,

(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-fluoro Ro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,

(-)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( 2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,

(-)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( Pyrimidin-2-yl) pyridin-2-yl] methanone,

(-)-[2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro Ro-2- (pyrimidin-2-yl) phenyl] methanone,

(-)-[2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl ] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [6- Methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,

[(2S, 4S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazinan-3- Il} [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[(2S *, 5S *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3 -Oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone,

(±)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,

(-)-[2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone,

(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro Ro-2- (pyrimidin-2-yl) phenyl] methanone,

(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methyl} -1,3-oxazolidin-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazolidin-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,

And (-)-[(2S *, 5R *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1, 3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone.

(8) A medicine containing the compound according to any one of (1) to (7) above, or a pharmaceutically acceptable salt thereof as an active ingredient.

(9) Sleep disorder, depression, anxiety disorder, panic disorder, ataxia, drug dependence, Alzheimer's disease, containing the compound according to any one of (1) to (7) above, or a pharmaceutically acceptable salt thereof as an active ingredient , Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, or drugs for the treatment or prevention of hypertension.

It has been found that the heteroaromatic methyl cyclic amine derivatives of the present invention exhibit affinity for OX receptors and antagonism to stimulation of receptors by physiological ligands.

The term used in this specification has the following meaning.

The "halogen atom" is a fluorine atom, a chlorine atom, a bromine atom, and an iodine atom.

"C _{1 -6} alkyl group" refers to a straight or represents C 1 -C 6 alkyl groups and branched-chain, such as methyl, ethyl, n- propyl, isopropyl, n- butyl, isobutyl, sec- butyl, tert-butyl, n-pentyl, isopentyl, neopentyl, tert-pentyl, 1-ethylpropyl, n-hexyl, isohexyl, neohexyl group, and the like.

The term "sleep disorder" in the present specification is an impairment at the time of incubation, a persistent sleep phase or awakening, and insomnia and the like are exemplified. In addition, the classification of insomnia includes elevation disorder, moderate arousal, early morning awakening, and sleep disturbance.

The term "pharmaceutically acceptable salt" in the present specification means a pharmaceutically acceptable acid addition salt, and examples of the acid used include salts with inorganic acids such as sulfuric acid, hydrochloric acid, hydrobromic acid, phosphoric acid and nitric acid, or Acetic acid, benzoic acid, oxalic acid, lactic acid, malic acid, tartaric acid, fumaric acid, maleic acid, citric acid, malonic acid, mandelic acid, gluconic acid, galactaric acid, glucoheptonic acid, glycolic acid, glutamic acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, salts with organic acids such as p-toluenesulfonic acid, camposulfonic acid, and naphthalene-2-sulfonic acid. Conversion from the vitreous body to the salt can be carried out by a conventional method.

In the compound of the present invention, preferred embodiments are illustrated below.

R ¹ is preferably a halogen atom or a C _{1 -6} alkyl group and a fluorine atom or a methyl group, and the compound is more preferably, a methyl group is more preferable compound.

R ² is preferably a triazolyl group or a pyrimidinyl group, and more preferably 1,2,3-triazol-2-yl group or pyrimidin-2-yl group.

R ³ is preferably a compound that is a halogen atom, more preferably a compound that is a fluorine atom or a chlorine atom, and more preferably a compound that is a fluorine atom.

R ⁴ is preferably a hydrogen atom or a methyl group.

n is preferably a compound of two.

In addition, when the compounds of the present invention form hydrates or solvates, they are also included within the scope of the present invention. Similarly, pharmaceutically acceptable salts of hydrates or solvates of the compounds of the invention are also included within the scope of the invention.

The compounds of the present invention include enantiomers, diastereomers, equilibrium compounds, mixtures in any ratio thereof, racemates, and the like.

The compound according to the present invention also includes compounds in which one or more hydrogen atoms, carbon atoms, nitrogen atoms, oxygen atoms, and halogen atoms are replaced with radioactive or stable isotopes. These labeled compounds are useful for biological analysis, such as metabolism and drug dynamics studies, and receptor ligands.

The compounds according to the invention can be administered orally or parenterally. The dosage forms thereof are tablets, capsules, granules, powders, powders, troches, ointments, creams, skin adhesives, emulsions, suspensions, suppositories, injections, etc., all of which are conventional formulation techniques (e.g., fifteenth) It can be manufactured by the method specified in the revised Japanese pharmacy. These dosage forms can be appropriately selected according to the patient's symptoms, age, weight, and purpose of treatment.

These formulations are pharmacologically acceptable carriers for compositions containing the compounds of the present invention, ie excipients (eg, crystalline cellulose, starch, lactose, mannitol), binders (eg hydroxypropylcellulose, polyvinyl Pyrrolidone), a lubricant (for example, magnesium stearate, talc), a disintegrant (for example, carboxymethylcellulose calcium), and other pharmacologically acceptable additives can be prepared.

The compound of the present invention can be administered orally or parenterally by dividing 0.001 to 500 mg once or several times a day as a single dose to an adult patient. In addition, this dosage can be appropriately increased or decreased depending on the type of disease to be treated, the patient's age, weight, and symptoms.

Representative methods for preparing the compound (I) of the present invention are shown in Schemes A and B below. The following method is an example of the method for preparing a compound of the present invention, and is not limited thereto. In addition, in the example of the following production method, the compound may form a salt that does not interfere with the reaction.

Scheme A

(Wherein, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ and R ⁴ are the same as above, A ¹ is a halogen atom, methanesulfonyloxy group, p-toluenesulfonyloxy group or Represents a trifluoromethanesulfonyloxy group, where n is 1 or 2)

Step A-1: Compound (3) can be obtained by condensation reaction of ethyl glyoxylate (1) and amine compound (2). The reaction in step A-1 can be carried out in the presence or absence of a base and a dehydrating agent such as molecuracive or anhydrous copper sulfate, in a solvent under conditions of reacting with an amine compound or a hydrochloride salt thereof. Examples of the base used in this reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, inorganic bases such as sodium hydroxide, potassium hydroxide and sodium hydrogen carbonate, and acetates such as sodium acetate and potassium acetate. have. Examples of the solvent used in this reaction include ether-based solvents such as tetrahydrofuran and 1,4-dioxane, non-protic polar solvents such as N, N-dimethylformamide and acetonitrile, and halogen-based solvents such as dichloromethane and chloroform. , Aromatic hydrocarbon-based solvents such as toluene, ethyl acetate, or mixed solvents thereof. This reaction can be performed at 0 ° C to 100 ° C.

Step A-2: Compound (5) can be obtained by a condensation reaction between compound (3) and carboxylic acid (4). The reaction in step A-2 can be carried out by a general amidation method of carboxylic acid. For example, after inducing carboxylic acid to a carboxylic acid halide such as carboxylic acid chloride or carboxylic acid bromide, the method of reacting with (3), reacting the carboxylic acid with (3) in the presence of a dehydrating condensing agent And methods. All of these reactions can be carried out in a solvent with or without a base. Thionyl chloride, oxalyl chloride, phosphorus oxychloride or phosphorus oxybromide is mentioned as a halogenating agent used in this reaction. Moreover, as the dehydrating condensing agent used in this reaction, 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC.HCl), [O- (7-azabenzotriazol-1-yl) -N, N, N ', N'-tramethyluronium hexafluorophosphate] (HATU), propanephosphonic acid anhydride, dicyclohexylcarbodiimide (DDC), diphenylphosphoryl azide (DPPA) ), Carbonyldiimidazole (CDI), and the like, and if necessary, activators such as 1-hydroxybenzotriazole and hydroxysuccinimide can be used. Examples of the solvent used in this reaction include ether-based solvents such as tetrahydrofuran and 1,4-dioxane, non-protic polar solvents such as N, N-dimethylformamide and acetonitrile, and halogen-based solvents such as dichloromethane and chloroform. , Aromatic hydrocarbon-based solvents such as toluene, ethyl acetate, or mixed solvents thereof. Examples of the base used in the reaction include organic amines such as pyridine, triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, sodium carbonate and sodium hydrogen carbonate. This reaction can be usually performed at 0 ° C to 150 ° C, preferably 0 ° C to 80 ° C.

Step A-3: Compound (6) can be obtained by a reduction reaction of the ester of compound (5). The reaction in step A-3 is hydrogenation in an alcohol-based solvent such as methanol or ethanol, an ether-based solvent such as tetrahydrofuran or 1,4-dioxane, or an aromatic hydrocarbon-based solvent such as toluene, or a mixed solvent thereof. It can be carried out under conditions to react with a reducing agent such as lithium aluminum, hydrogenated diisobutylaluminum, sodium borohydride, lithium borohydride, and the like. This reaction can be carried out at -80 ° C to 150 ° C, preferably 0 ° C to 25 ° C.

Step A-4: Compound (7) can be obtained by converting the hydroxyl group of compound (6) into a general leaving group. Examples of the reaction in step A-4 include chloroation, bromolation, iodation, methanesulfonyloxylation, and p-toluenesulfonyloxylation. As an example of the chloroation reaction, for example, a method of dissolving using methanesulfonyl chloride or the like and then substituting with a chlorine atom may be mentioned. In addition, there may be mentioned a method using carbon tetrachloride and triphenylphosphine, a method using thionyl chloride or phosphorus oxychloride. At this time, chlorides such as sodium chloride and potassium chloride can be added. As an example of a bromination reaction, the method using carbon tetrabromide and triphenylphosphine is mentioned, for example. Examples of the iodization reaction include, for example, a method using iodine, triphenylphosphine and imidazole. The methanesulfonyloxylation and p-toluenesulfonyloxylation can be performed using, for example, methanesulfonyl chloride, p-toluenesulfonyl chloride, or the like. In these reactions, a suitable base can be added. Examples of the base to be added include organic bases such as triethylamine and diisopropylethylamine, and inorganic bases such as potassium carbonate, for example. Examples of the reaction solvent include ether-based solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as N, N-dimethylformamide and acetonitrile, and halogen-based solvents such as dichloromethane and chloroform. , Acetonitrile or a mixed solvent thereof, the reaction can be carried out under temperature conditions near -80 ° C to near the boiling point of the solvent.

Step A-5: Compound (9) can be obtained by reacting compound (7) with compound (8). The reaction in step A-5 is alcohol-based solvents such as methanol and ethanol, ether-based solvents such as tetrahydrofuran and 1,4-dioxane, aprotic properties such as N, N-dimethylformamide and acetonitrile. Halogen-based solvents such as polar solvents, dichloromethane, and chloroform, dimethyl sulfoxide, acetonitrile, water, or a mixed solvent thereof, inorganic bases such as sodium hydride, sodium hydroxide, sodium carbonate, potassium carbonate, cesium carbonate, and sodium ethoxy In the presence of an alkali base such as a seed or potassium tert-butoxide or an organic base such as a lower alkoxide of an alkaline earth metal, the process proceeds under temperature conditions near -80 ° C to near the boiling point of the solvent.

Scheme B

(In the formula, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ and R ⁴ are the same as above, R ⁵ , R ⁶ are alkoxy groups, A ² is a halogen atom, methanesulfonyl oxide Period, p-toluenesulfonyloxy group or trifluoromethanesulfonyloxy group)

Step B-1: Compound (12) can be obtained by reacting compound (10) with compound (11). The reaction in step B-1 can be carried out in accordance with the same reaction conditions as in step A-5.

Step B-2: Compound (13) can be obtained from compound (12). The reaction in step B-2 is such as a hydrous alcohol solvent such as hydrous methanol or hydrous ethanol, an ether solvent such as tetrahydrofuran or 1,4-dioxane, a halogen solvent acetone such as dichloromethane or chloroform, and the like. It can be carried out under conditions to react with an acid such as hydrochloric acid, trifluoroacetic acid, or p-toluenesulfonic acid in a ketone solvent, water or a mixed solvent thereof. This reaction can be performed at 0 ° C to 80 ° C.

Step B-3: Compound (15) can be obtained by a condensation reaction between compound (13) and compound (14). The reaction in step B-3 can be carried out in accordance with the same reaction conditions as in step A-1.

Step B-4: Compound (16) can be obtained by a condensation reaction between compound (4) and compound (15). The reaction in step B-4 can be carried out in accordance with the same reaction conditions as in step A-2.

Scheme C

(In the formula, X ¹ , X ² , R ¹ , R ² , R ³ and R ⁴ are as described above, and R ⁵ and R ⁶ represent an alkoxy group)

Step C-1: Compound (19) can be obtained by the amide oximeation reaction of compound (17). The reaction in step C-1 can be obtained under conditions in which the nitrile body 17 is reacted with hydroxylamine 18 or its hydrochloride in an alcoholic solvent such as methanol or ethanol. This reaction can be performed at 0 ° C to 100 ° C.

Step C-2: Compound (21) can be obtained by oxadiazole cyclization reaction between compound (19) and compound (20). The reaction in step C-2 is an ether-based solvent such as tetrahydrofuran or 1,4-dioxane, an aprotic polar solvent such as N, N-dimethylformamide, or a halogen-based solvent such as dichloromethane or chloroform. , Carboxylic acid (20) and 1-ethyl-3- (3-dimethylaminopropyl) carbodiimide hydrochloride (EDC, HCl) in aromatic hydrocarbon solvents such as toluene, ethyl acetate, acetonitrile, or a mixed solvent thereof ), Dicyclohexylcarbodiimide (DDC) and carbonyldiimidazole (CDI). This reaction can be usually carried out at 0 ° C to 150 ° C, preferably 0 ° C to 90 ° C.

Step C-3: Compound (22) can be obtained by acid hydrolysis of compound (21). The reaction in step C-3 can be carried out according to the same reaction conditions as in step B-2.

Step C-4: Compound (23) can be obtained by a condensation reaction between compound (14) and compound (22). The reaction in step C-4 can be carried out in accordance with the same reaction conditions as in step A-1.

Step C-5: Compound (24) can be obtained by a condensation reaction between compound (4) and compound (23). The reaction in step C-5 can be carried out in accordance with the same reaction conditions as in step A-2.

Scheme D

(Wherein, X ¹ , X ² , R ¹ , R ³ and R ⁴ are the same as above, R ⁸ is a triazolyl group, pyridyl group or halogen atom, A ³ represents a halogen atom)

Step D-1: Compound (27) can be obtained by a nucleophilic reaction or a coupling reaction between compound (25) and compound (26). The reaction in step D-1 can be carried out in accordance with the nucleophilic reaction conditions similar to those in step A-5. The coupling reaction can be carried out by a general method of carrying out aromatic ring substitution of an azole compound with a nitrogen atom using a catalyst and a ligand in the presence of a base. For example, the method described in [Synlett, 2003, 15, 2428-2439.] Or a method similar thereto can be cited. Examples of the catalyst used in this reaction include copper catalysts such as copper (0), copper (I) iodide, copper (I) chloride, and copper (I) oxide. As the ligand used in this reaction, N, N'-dimethylethylenediamine, N, N'-dimethylcyclohexane-1,2-diamine, 2-aminopyridine, 1,10-phenanthroline, 2-hydroxybenzaldehyde oxime And the like. Examples of the base used in the reaction include potassium carbonate, potassium phosphate, potassium hydroxide, tert-butoxy potassium, cesium carbonate, sodium carbonate, sodium hydrogen carbonate, sodium acetate, sodium methoxide, and tetrabutylammonium hydroxide. . Examples of the solvent used in this reaction include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotons such as N, N-dimethylformamide, dimethyl sulfoxide and acetonitrile. Sexual polar solvents, halogen-based solvents such as dichloromethane and chloroform, aromatic hydrocarbon-based solvents such as toluene, water or mixed solvents thereof. This reaction can be usually performed at 0 ° C to 150 ° C, preferably at 25 ° C to 100 ° C.

Step D-2: Compound (28) can be obtained by an oxidation reaction of the hydroxyl group of compound (27). In step D-2, the reaction is a halogen-based solvent such as dichloromethane or chloroform, an aprotic polar solvent such as dimethyl sulfoxide or acetonitrile, a desmatine reagent, a high molecular weight iodine compound such as 2-iodooxybenzoic acid. , Chromate such as pyridinium chlorochromate, pyridinium dichromate, and oxidizing agents such as tetrapropylammonium perrunate and manganese dioxide. This reaction can be carried out at 0 ° C to 150 ° C, preferably 25 ° C to 80 ° C.

Step D-3: Compound (29) can be obtained by a condensation reaction between compound (14) and compound (28). The reaction in step D-3 can be carried out in accordance with the same reaction conditions as in step A-1.

Step D-4: Compound (31) can be obtained by a condensation reaction between compound (29) and compound (30). The reaction in step D-4 can be carried out in accordance with the same reaction conditions as in step A-2.

Step D-5: Compound (33) can be obtained by a coupling reaction between compound (31) and compound (32). The reaction in step D-5 is a Stille couple using an organotin compound in an aprotic polar solvent such as N, N-dimethylformamide, an aromatic hydrocarbon solvent such as toluene, or a mixed solvent thereof. It can be obtained by reacting under the conditions of a ring reaction. A comprehensive overview of the Stille coupling reaction can be found, for example, in Angew. Chem. Int. Ed., 43, 4704, (2004).

Scheme E

(Wherein, X ¹ , X ² , R ¹ , R ² , R ³ , R ⁴ and A ³ are as described above, and R ⁷ is a general protecting group of carboxylic acids, for example, by JFW McOmie, Protective Groups in Organic Chemistry.] and [TW Greene and PGMWuts represents a group such as that described, Protective groups in Organic Synthesis.], for example, represent a C _{1 -6} alkyl group, benzyl group, etc.)

Step E-1: Compound (34) can be obtained by nucleophilic reaction or coupling reaction of compound (26) and compound (33). The reaction in step E-1 can be carried out in accordance with the same reaction conditions as in step D-1.

Step E-2: Compound (35) can be obtained by a reduction reaction of the ester of compound (34). The reaction in step E-2 is lithium hydride in an alcohol-based solvent such as methanol or ethanol, an ether-based solvent such as tetrahydrofuran or 1,4-dioxane, or an aromatic hydrocarbon-based solvent such as toluene or a mixed solvent thereof. It can be carried out under conditions to react with a reducing agent such as aluminum, hydrogenated diisobutylaluminum, sodium borohydride, lithium borohydride, and the like. This reaction can be carried out at -80 ° C to 150 ° C, preferably 0 ° C to 25 ° C.

Step E-3: Compound (36) can be obtained by the oxidation reaction of the hydroxyl group of compound (35). The reaction in step E-3 can be carried out in accordance with the same reaction conditions as in step D-2.

Step E-4: Compound (38) can be obtained by the Witrich reaction of compound (36) and compound (37). In the reaction in step E-4, methoxymethyltriphenylphosphonium chloride is an ether-based solvent such as tetrahydrofuran or 1,4-dioxane, an aromatic hydrocarbon-based solvent such as toluene, or a mixed solvent thereof. After treatment with a base such as sodium hydride, potassium hydride, potassium tert-butoxy, sodium bis (trimethylsilyl) amide, lithium bis (trimethylsilyl) amide, it can be carried out under conditions of reacting with an aldehyde. This reaction can be carried out at 0 ° C to 120 ° C. The produced enoether can be subjected to hydrolysis using inorganic acids such as hydrochloric acid, trifluoroacetic acid, and p-toluenesulfonic acid, organic acids, and Lewis acids such as mercury acetate. This reaction can be performed at 0 ° C to 80 ° C.

Step E-5: Compound (39) can be obtained by a condensation reaction between compound (14) and compound (38). The reaction in step E-5 can be carried out in accordance with the same reaction conditions as in step A-1.

Step E-6: Compound (40) can be obtained by condensation reaction between compound (4) and compound (39). The reaction in step E-6 can be carried out in accordance with the same reaction conditions as in step A-2.

Scheme F

(Wherein, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ² , R ³ and R ⁴ are the same as above)

Step F-1: Compound (9) can be obtained by Mitsunobu reaction of compound (6) and compound (8). The reaction in step F-1 is triphenylphosphine / azodicarbonic acid in an ether-based solvent such as tetrahydrofuran or 1,4-dioxane, a halogen-based solvent such as dichloromethane or chloroform, or a mixed solvent thereof. Diethyl (DEAD), cyano methylene tributyl phosphoran (CMBP), and the like can be carried out under conditions to react. This reaction can be carried out at 0 ° C to 150 ° C, preferably 0 ° C to 80 ° C.

Scheme G

(Wherein, X ¹ , X ² , Y ¹ , Y ² , R ¹ , R ³ and R ⁴ are the same as above, and A ⁴ represents a halogen atom)

Step G-1: Compound (42) can be obtained by condensation reaction between compound (15) and compound (41). The reaction in step G-1 can be carried out in accordance with the same reaction conditions as in step A-2.

Step G-2: Compound (43) can be obtained by a coupling reaction between compound (32) and compound (42). The reaction in step G-2 can be carried out in accordance with the same reaction conditions as in step D-5.

Scheme H

(Wherein, X ¹ , R ¹ , R ² and R ⁴ are as above)

Step H-1: Compound (45) can be obtained by separating compound (44) from optical isomers. Step H-1 can be directly separated by HPLC using a polysaccharide derivative chiral column or a protein-coupled chiral column. In addition, a method using an enzymatic method, a chemical synthesis method, or a method of converting a diastereomer to an alcohol by reacting an optical resolving agent may be mentioned. In the method using the enzymatic method, the optically active substance can be prepared by dissolving the compound in a solvent and acylating an alcohol by adding a lipase in the presence of an acid alkenyl ester. As the lipase, microorganism-derived or animal-derived substances can be used, and for example, pig pancreatic lipases, Candida genus, Pseudomonas genus, Aspergillus genus and the like can be used. Examples of the acid alkenyl ester include vinyl acetate, vinyl propionate, and vinyl hexanoate. Examples of the reaction solvent include ether-based solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as acetonitrile, halogen-based solvents such as dichloromethane and chloroform, aromatic hydrocarbon-based solvents such as toluene, water, or those. And mixed solvents. This reaction can be carried out at 20 ° C to 50 ° C, preferably 25 ° C to 35 ° C.

In the synthesis method using a chemical method, an optically active substance can be produced by asymmetric esterification using an asymmetric catalyst and an ester agent. Examples of the asymmetric catalyst include an optically active bisoxazoline-copper complex. Examples of the optically active bis oxazoline catalyst are (R, R) -2,2'-isopropylidenebis (4-phenyl-2-oxazoline) or (S, S) -2,6-bis (4-isopropyl- 2-oxazolin-2-yl) pyridine and the like, and examples of the copper catalyst include copper halide such as copper (II) trifluoromethanesulfonate, copper (II) chloride, and copper (II) bromide. As an ester agent, benzoyl chloride, acetyl chloride, etc. are mentioned. Examples of the reaction solvent include alcohol solvents such as methanol and ethanol, ether solvents such as tetrahydrofuran and 1,4-dioxane, aprotic polar solvents such as acetonitrile, halogen solvents such as dichloromethane and chloroform, and toluene. And aromatic hydrocarbon-based solvents or mixed solvents thereof. This reaction can be carried out at -30 ° C to 60 ° C, preferably -10 ° C to 30 ° C.

In the diastereomer separation method, the compound is chiral carboxyl such as (S) -5-allyl-2-oxabicyclo [3.3.0] oct-8-ene or (-)-O-acetyl-D-mandelic acid. After reacting an optical resolving agent containing an acid to separate the diastereomer by fractional crystallization or column chromatography, acids such as hydrochloric acid, trifluoroacetic acid and p-toluenesulfonic acid, potassium carbonate, potassium phosphate, potassium hydroxide, etc. The optically active agent can be prepared by removing the optical resolving agent under the basic conditions of. This reaction can be carried out at 0 ° C to 80 ° C, preferably 0 ° C to 30 ° C.

[Example]

Hereinafter, the present invention will be described in more detail with reference examples, examples, and test examples, but these are not intended to limit the present invention and may be changed within a scope not departing from the scope of the present invention.

In the following reference examples and examples, when using column chromatography to purify, "KP-Sil" is Biotage's SNAP cartridge (Cartridge) KP-Sil, and "HP-Sil" is Biotage's SNAP The cartridge HP-Sil, "KPNH" used SNAP cartridge KP-NH from Biotage. Biotage's Isolate Phase Separator was used for the "ISOLUTE Phase Separator" during the post-processing operation of the following Reference Examples and Examples.

In the following Reference Examples and Examples, silica gel 60F254 (manufactured by Merck) was used for purification by thin layer chromatography (PTLC).

In the following reference examples and examples, purification by preparative high-speed liquid chromatography (HPLC) was performed under the following conditions. However, in the case of a compound having a basic functional group, when trifluoroacetic acid is used in this operation, a neutralization operation or the like to obtain a free body may be performed.

Machine: Gilson's Trilution LC

Column: Waters SunFire prep C18 OBD 5.0 µm 30 × 50 mm or YMC YMC-Actus Triant 5.0 µm 50 × 30 mm

Solvent: Liquid A; 0.1% trifluoroacetic acid-containing water, Liquid B; Acetonitrile with 0.1% trifluoroacetic acid

Gradient: 0 minutes (A solution / B solution = 90/10), 11 minutes (A solution / B solution = 20/80), 12 to 13.5 minutes (A solution / B solution = 5/95)

Flow rate: 40 mL / min

Detection method: UV 254nm

In the following reference examples and examples, high-speed liquid chromatography mass spectrum (LCMS) was measured under the following two conditions.

Condition 1

Measuring machine: Agilent 2900 and Agilent 6150 from Agilent

Column: Waters Corporation Acquity CSH C18 1.7㎛ 2.1 × 50㎜

Solvent: Liquid A; 0.1% formic acid-containing water, Liquid B; Acetonitrile with 0.1% formic acid

Gradient: 0 minutes (A solution / B solution = 80/20), 1.2 to 1.4 minutes (A solution / B solution = 1/99)

Flow rate: 0.8 mL / min, detection method: UV 254 nm

Ionization method: Electron Spray Ionization (ESI)

Condition 2

Measuring machine: Shimadzu LCMS-2010EV

Column: Shimadzu Corporation Shim-pack XR-ODS 2.2㎛ 2.0㎜I.D. × 30㎜

Solvent: Liquid A; 0.1% formic acid-containing water, Liquid B; Acetonitrile with 0.1% formic acid

Gradient: 0 minutes (A solution / B solution = 90/10), 1 minute (A solution / B solution = 60/40), 2 minutes (A solution / B solution = 0/100), 2.5 minutes (A solution / B amount = 0/100)

Flow rate: 0.6 mL / min, detection method: UV 254 nm

Ionization method: Electron Spray Ionization (ESI) and Atomospheric Pressure Chemical Ionization (APCI)

In the following reference examples and examples, the mass spectrum (MS) was measured under the following conditions.

MS measuring instrument: LCMS-2010EV from Shimadzu or Platform LC from micromass

In the following examples, analysis of the racemate was carried out under any of the following 13 types of conditions.

Condition 1

Measuring machine: Agilent 1100

Column: Chiralpak AD-3 (Daicel, 4.6 mm * 250 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 30/70

Condition 2

Measuring machine: Waters 2695 and 2998

Column: Chiral Pack IB (Daicel, 4.6 mm * 250 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 90/10

Condition 3

Measuring machine: Waters 2695 and 2998

Column: Chiral Pack IB (Daicel, 4.6 mm * 250 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / 2-propanol = 30/70

Condition 4

Measuring machine: Agilent 1100

Column: Chiral Pack AD-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 20/80

Condition 5

Measuring machine: Agilent 1100

Column: Chiral Pack IB-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 50/50

Condition 6

Measuring machine: Waters 996 and 2795 from Waters

Column: Chiral Pack AD-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / 2-propanol = 0/100

Condition 7

Measuring machine: Agilent 1100

Column: Chiral Pack IB-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 70/30

Condition 8

Measuring machine: Waters 996 and 2795 from Waters

Column: Chiral Pack IB-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / 2-propanol = 30/70

Condition 9

Measuring machine: Agilent 1100

Column: Chiral Pack AD-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 30/70

Condition 10

Measuring machine: Agilent 1100

Column: Chiral Pack IB-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 90/10

Condition 11

Measuring machine: Agilent 1100

Column: Chiral Pack IB-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / ethanol = 80/20

Condition 12

Measuring machine: Waters 996 and 2795 from Waters

Column: Chiral Pack ID-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / 2-propanol = 50/50

Condition 13

Measuring machine: Waters 996 and 2795 from Waters

Column: Chiral Pack IA-3 (Daicel, 4.6 mm * 150 mm)

Flow rate: 1.0 mL / min

Mobile phase: Hexane / 2-propanol = 20/80

In the following examples, the optical intensity analysis was measured under the following conditions.

Measuring machine: Nippon Bunkosa JASCO P-2300

In the following reference examples and examples, the microwave reaction apparatus was implemented using an initiator (Biotage AB).

In the following reference examples and examples, the compound names were named by ACD / Name (ACD / Labs 12.01, Advanced Chemistry Development Inc.).

In Reference Examples and Examples, the following terms and reagents are indicated as follows.

Na ₂ SO ₄ (sodium anhydrous sulfate), MgSO ₄ (magnesium anhydride), Cs ₂ CO ₃ (cesium carbonate), NaHCO ₃ (sodium hydrogen carbonate), TFA (trifluoroacetic acid), THF (tetrahydrofuran), DMF (N, N-dimethylformamide), NMP (N-methyl-2-pyrrolidone) EtOAc (ethyl acetate), CHCl ₃ (chloroform), HATU [O- (7-azabenzotriazol-1-yl ) -N, N, N ', N'-tetramethyluronium hexafluorophosphate], DIPEA (N, N-diisopropylethylamine), TEA (triethylamine), MsCl (methanesulfonyl chloride), NaBH ₄ (sodium borohydride), LiBH ₄ (lithium borohydride).

Reference Example 1: (±) -ethyl3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate

To a solution of CHCl ₃ (260 mL) in ethyl glyoxylate (polymeric form, 47% toluene solution) (13.4 mL, 63.5 mol), activated Molycular Sieve 4A (200 g), 2-aminoethanol (4.0 mL, 66.1 mmol) Was added and stirred at room temperature for 24 hours. After filtration separation of the Molecular Sieve 4A by filtration through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain a pale yellow oily substance. To a solution of CHCl ₃ (130 mL) of 5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoic acid (2.7 g, 13.2 mmol), thionyl chloride (1.4 mL, 19.8 mmol) was added. It was added dropwise and stirred at 75 ° C for 5 hours. After cooling to room temperature, the solvent and excess thionyl chloride were distilled off under reduced pressure. To a solution of CHCl ₃ (100 mL) of the obtained residue, ice-water was cooled, TEA (3.7 mL, 26.4 mmol) and a CHCl ₃ (30 mL) solution of the pale yellow oil obtained by the above reaction were added, heated to room temperature, and stirred for 3 hours. Water was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150 g, hexane / EtOAc = 88/12 to 0/100) to obtain the title compound (3.6 g) (pale yellow oil).

MS (ESI / APCI Dual pos.) M / z: 331 [M + H] ⁺

Reference Example 2: (±)-[2- (hydroxymethyl) -1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2- 1) phenyl] methanone

(±) -ethyl3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxyl obtained in Reference Example 1 To a solution of rate (4.0 g, 12.1 mmol) in MeOH (60 mL), NaBH ₄ (4.6 g, 121 mmol) was added little by little under ice water cooling and stirred for 1 hour. After heating up to room temperature, the mixture was stirred for 1 hour. The solvent was distilled off under reduced pressure, and saturated aqueous ammonium chloride solution was added to the reaction mixture, followed by extraction with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, hexane / EtOAc = 88/12 to 0/100) to obtain the title compound (3.6 g) (colorless oil).

MS (ESI / APCI Dual pos.) M / z: 289 [M + H] ⁺

Reference Example 3: (±) -ethyl3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinan-2-carboxylate

Ethyl glyoxylate (polymer type, 47% toluene solution) (4.3 mL, 20.4 mol), 3-aminopropan-1-ol (1.6 mL, 20.4 mmol), 5-methyl-2- (2H-1,2, 3-Triazol-2-yl) benzoic acid (1.0 g, 4.9 mmol) was used, and the title compound (1.3 g) was obtained by the same method as in Reference Example 1 (colorless solid).

MS (ESI pos.) M / z: 367 [M + Na] ⁺

Reference Example 4: (±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl ) Phenyl] methanone

(±) -ethyl3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane-2-carboxylate obtained in Reference Example 3 A THF solution of LiBH ₄ (0.97 mL, 2.9 mmol) was added to a solution of (0.50 g, 1.5 mmol) THF (5 mL) and stirred at room temperature for 2 hours. Water was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 88/12 to 0/100) to obtain the title compound (0.34 g) (colorless oil).

MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 5: Ethyl (2RS, 5S) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine -2-carboxylate

Ethyl glyoxylate (polymer type, 47% toluene solution) (0.5 mL, 2.4 mmol), (2S) -1-aminopropan-2-ol (0.18 mL, 2.4 mmol), 5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzoic acid (0.20 g, 0.98 mmol) was used, and the title compound (0.11 g) was obtained by the same method as in Reference Example 1 (colorless oily substance).

MS (ESI / APCI Dual pos.) M / z: 345 [M + H] ⁺

Reference Example 6: Ethyl (2RS, 5R) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine -2-carboxylate

Ethyl glyoxylate (polymer type, 47% toluene solution) (0.50 mL, 2.4 mmol), (2R) -1-aminopropan-2-ol (0.18 mL, 2.4 mmol), 5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzoic acid (0.20g, 0.98mmol) was used, and the title compound (0.14g) was obtained by the same method as in Reference Example 1 (colorless oily substance).

MS (ESI / APCI Dual pos.) M / z: 345 [M + H] ⁺

Reference Example 7: [(2S, 4R) -2- (hydroxymethyl) -4-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone

Ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.5 mmol), (2R) -2-aminopropan-1-ol (0.73 mL, 9.5 mmol), 5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzoic acid (1.0g, 4.9mmol) was used, and ethyl (2RS, 4R) -4-methyl-3- [5-in the same manner as in Reference Example 1 A diastereomeric mixture of methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained. The resulting diastereomeric mixture was purified by thin layer chromatography (1 mm, hexane / EtOAc = 66/34) to give ethyl (2S, 4R) -4-methyl-3- [5-methyl-2- (2H-1,2) , 3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained (colorless oil). Using the obtained colorless oily substance as a raw material, the title compound (0.041 g) was obtained by the same method as in Reference Example 4 (colorless oily substance).

MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 8: [(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3 -Triazol-2-yl) phenyl] methanone

Ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.5 mmol), (2S) -2-aminopropan-1-ol (0.73 mL, 9.5 mmol), 5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzoic acid (1.0g, 4.9mmol) was used, and ethyl (2RS, 4S) -4-methyl-3- [5-in the same manner as in Reference Example 1 A diastereomeric mixture of methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained. The resulting diastereomeric mixture was purified by thin layer chromatography (1 mm, hexane / EtOAc = 66/34) to give ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- (2H-1,2) , 3-triazol-2-yl) benzoyl] -1,3-oxazolidine-2-carboxylate was obtained (colorless oil). Using the obtained colorless oily substance as a raw material, the title compound (0.19 g) was obtained by the same method as in Reference Example 4 (colorless solid).

MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 9: 5-fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] pyridine

1- (tetrahydro-2H-pyran-2-yl) -5- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole (100.5 g, 0.36 mol), 2-bromo-5-fluoropyridine (56.5 g, 0.33 mol) and Pd (PPh ₃ ) ₄ (38.0 g, 32.6 mmol) of ethanol (300 mL) -toluene (300 mL) mixed A 2M Na ₂ CO ₃ aqueous solution (0.49L, 0.99mol) was added to the solution, and the mixture was heated to reflux for 2 hours. After cooling at room temperature, water and EtOAc were added to the reaction mixture, which was stirred at room temperature for 30 minutes, and extracted with EtOAc. The organic layer was washed with a saturated aqueous sodium chloride solution, dried over MgSO _4, and then the drying agent was filtered off, followed by adding NH silica gel (400 g) and stirring for 15 hours. This was filtered with an acidic silica gel (n-hexane: AcOEt = 1: 1 → AcOEt), and the solvent was evaporated under reduced pressure to obtain the title compound (100 g) (pale yellow oil).

MS (ESI pos.) M / z: 248 [M + H] ⁺

Reference Example 10: 5-fluoro-2- (1H-pyrazol-3-yl) pyridine

5-fluoro-2- [1- (tetrahydro-2H-pyran-2-yl) -1H-pyrazol-5-yl] pyridine (81.2 g, 0.33 mol) of methanol (250 mL) obtained in Reference Example 9 To the solution, 4M HCl-EtOAc solution (0.25 L, 0.96 mol) was added and stirred at room temperature for 16 hours. The solvent was distilled off under reduced pressure, and EtOAc (500 mL) was added to the residue, followed by heating to reflux for 1 hour. After cooling to room temperature, ice-cooling, the precipitate was filtered off and dried to obtain the hydrochloride (colorless solid) of the title compound. Water (700 mL) and EtOAc (350 mL) were added to the obtained hydrochloride, stirred for 30 minutes, and then separated. The obtained organic layer was extracted three times using 1.2M hydrochloric acid (100 mL). The aqueous layers were combined, adjusted to pH = 12 using 8M NaOH aqueous solution, and extracted with CHCl ₃ . The extracted organic layer was passed through an isolute phase separator, and the solvent was distilled off under reduced pressure. Diisopropyl ether (300 mL) was added to the obtained residue, and the mixture was heated to reflux for 2 hours. After cooling at room temperature, ice-cooling, the precipitate was filtered off and dried to obtain the title compound (44.9 g) (light pink solid).

MS (ESI pos.) M / z: 164 [M + H] ⁺

Reference Example 11: 5-fluoro-2- (1H-pyrazol-4-yl) pyridine

tert-butyl4- (4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-yl) -1H-pyrazole-1-carboxylate (15.4 g, 52.5 mmol) ) And 2-bromo-5-fluoropyridine (8.4 g, 47.7 mmol) in a 1,4-dioxane (100 mL) solution of Pd (PPh ₃ ) ₄ (5.5 g, 4.77 mmol), 2M Na ₂ CO ₃ An aqueous solution (71.6 mL, 0.14 mol) was added, stirred at 100 ° C. for 3 hours, and then stirred at room temperature for 72 hours. Water was added to the reaction mixture, and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. A small amount of EtOAc was added to the obtained residue, filtered and dried to obtain the title compound (4.9 g) (colorless solid).

MS (ESI pos.) M / z: 164 [M + H] ⁺

Reference Example 12: 2- [1- (2,2-diethoxyethyl) -1H-pyrazol-3-yl] -5-fluoropyridine

Cs ₂ CO ₃ (57.3 g, 0.18 mol), 2 in a DMF (195 mL) solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (11.7 g, 58.6 mmol) obtained in Reference Example 10 -Bromo-1,1-diethoxyethane (11.5 mL, 76.2 mmol) was stirred at 80 ° C for 18 hours. After cooling to room temperature, water was added and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 88/12 to 35/65) to obtain the title compound (8.2 g) (colorless oily phase).

MS (ESI pos.) M / z: 280 [M + H] ⁺

Reference Examples 13 to 15 were obtained by the same method as Reference Example 12. Table 1 shows the structural formulas, compound names, and MS data of the obtained compounds.

Reference Example 16: Ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane- 2-carboxylate

To a solution of (3R) -3-aminobutanoic acid (1.0 g, 9.7 mmol) in THF (10 mL) was added 0.9 mol / L borane-THF solution (32.3 mL, 29.1 mmol) dropwise over 1 hour under ice bath cooling. Stir at room temperature for 20 minutes. It heated up to 80 degreeC, and also heated and stirred for 6 hours. Methanol was added under ice bath cooling, stirred for 30 minutes, and then concentrated under reduced pressure. Obtained (3R) -3-aminobutan-1-ol and ethyl glyoxylate (polymer type, 47% toluene solution) (2.0 mL, 9.7 mmol), 5-methyl-2- (2H-1,2,3- Diazol-2-yl) benzoic acid (0.50 g, 2.5 mmol) was used, and a diastereomeric mixture was obtained by the same method as in Reference Example 1 (colorless oily substance). The diastereomeric mixture obtained was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 90/10 to 0/100) to obtain the title compound (0.37 g) as a low-polar compound (colorless oil).

MS (ESI pos.) M / z: 359 [M + H] ⁺

Reference Example 17: [(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3- Triazole-2-yl) phenyl] methanone

Ethyl (2S, 4S) -4-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 16 2-carboxylate (0.37 g, 1.0 mmol) was used, and the title compound (0.068 g) was obtained by the same method as in Reference Example 2 (colorless solid).

MS (ESI pos.) M / z: 317 [M + H] ⁺

Reference Example 18: Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinan- 2-carboxylate

3-amino-2-methylpropan-1-ol (0.10 g, 1.1 mmol), ethyl glyoxylate (polymeric form, 47% toluene solution) (2.0 mL, 9.7 mmol), 5-methyl-2- (2H- 1,2,3-triazol-2-yl) benzoic acid (0.5g, 2.5mmol) was used, and the title compound (0.13g) was obtained by the same method as in Reference Example 1 (colorless oily substance).

MS (ESI pos.) M / z: 359 [M + H] ⁺

Reference Example 19: N-hydroxy-3,3-dimethoxypropanimideamide

NaHCO ₃ (3.8 g, 45.6 mmol) was added to a MeOH (70 mL) solution of hydroxylamine monohydrochloride (3.2 g, 45.6 mmol), stirred at room temperature for 30 minutes, and then 3,3-dimethoxypropanenitrile (5.0 g, 43.4 mmol) of MeOH (30 mL) solution was added dropwise. The mixture was stirred at 80 ° C for 15 hours. After cooling to room temperature, the resulting salt was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 100 g, CHCl ₃ / MeOH = 99/1 to 90/10) to give the title compound (4.5 g) (pale yellow oil).

MS (ESI pos.) M / z: 171 [M + Na] ⁺

Reference Example 20: 2- [3- (2,2-dimethoxyethyl) -1,2,4-oxadiazol-5-yl] -5-fluoropyridine

5-Fluoropyridine-2-, which was stirred with a DMF (3 mL) solution of N-hydroxy-3,3-dimethoxypropanimideamide (1.0 g, 6.8 mmol) obtained in Reference Example 19 at 40 ° C for 1 hour. It was added to a DMF (4 mL) solution of carboxylic acid (1.0 g, 7.1 mmol) and carbonyldiimidazole (1.3 g, 8.1 mmol) and stirred for 30 minutes. The reaction solution was heated to 90 ° C and stirred for 15 hours. Water was added to the reaction mixture, and extracted with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 75/25 to 0/100) to obtain the title compound (1.2 g) (colorless solid).

MS (ESI pos.) M / z: 254 [M + H] ⁺

Reference Example 21: 3- (2,2-dimethoxyethyl) -5- (4-fluorophenyl) -1,2,4-oxadiazole

N-hydroxy-3,3-dimethoxypropanimideamide (1.0g, 6.8mmol) and 4-fluorobenzoic acid (0.99g, 7.1mmol) obtained in Reference Example 19 were used as raw materials in the same manner as in Reference Example 20. The title compound (1.4 g) was obtained by (colorless oily substance).

MS (ESI pos.) M / z: 253 [M + H] ⁺

Reference Example 22: 2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol

Cs ₂ CO ₃ (9.7) in a solution of 2- (1H-pyrazol-4-yl) ethanol (1.0 g, 8.9 mmol) and 2,5-difluoropyridine (0.89 mL, 9.8 mmol) acetonitrile (45 mL) g, 17.8 mmol) was added and stirred at 80 ° C. for 3 hours. After cooling to room temperature, water was added to the reaction mixture, and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 90/10 to 30/70) to obtain the title compound (0.63 g) (colorless solid).

MS (ESI pos.) M / z: 208 [M + H] ⁺

Reference Example 23: (±)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) (2-io Figure-5-methylphenyl) methanone

TFA (0.42 mL) in a solution of CHCl ₃ (3 mL) of 1- (2,2-diethoxyethyl) -3- (4-fluorophenyl) -1H-pyrazole (0.16 g, 0.57 mmol) obtained in Reference Example 14 , 5.7mmol), and stirred at 35 ° C for 6 hours. TFA (0.14 mL, 0.19 mmol) was added and stirred at 35 ° C. for 6 hours. After cooling to room temperature, NaHCO ₃ aqueous solution was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off. The solvent was distilled off under reduced pressure to obtain a colorless oil. To the obtained colorless oily substance in a solution of CHCl ₃ (3 mL), activated Molecular 4A (0.60 g) and 3-aminopropan-1-ol (0.044 mL, 0.57 mmol) were added and stirred at room temperature for 24 hours. After filtering the Molecular Sieve 4A by filtration through Celite (registered trademark), the solvent was distilled off under reduced pressure to obtain a pale yellow oily substance. 2-iodo-5-methyl-benzoyl chloride CHCl ₃ (5mL) and ice-water cooling, TEA (0.20mL, 1.4mmol) as a light yellow oil water CHCl ₃ (2mL) obtained by the above reaction to a solution of (0.19g, 0.69mmol) The solution was added, and the temperature was raised to room temperature and stirred for 15 hours. Water was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 80/20 to 0/100) to obtain the title compound (0.19 g) (pale yellow oil).

MS (ESI pos.) M / z: 506 [M + H] ⁺

Reference Example 24: (±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) (2-io Figure-5-methylphenyl) methanone

1- (2,2-diethoxyethyl) -4- (4-fluorophenyl) -1H-pyrazole (1.0 g, 3.6 mmol) obtained in Reference Example 15 was used as a raw material in the same manner as in Reference Example 23. The title compound (1.2 g) was obtained (colorless oily substance).

MS (ESI pos.) M / z: 506 [M + H] ⁺

Reference Example 25: (±)-(2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl) (2-iodo-5-methylphenyl) methanone

2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.21 g, 1.0 mmol) obtained in Reference Example 22 in dimethyl sulfoxide (5 mL) solution 2- Iodooxybenzoic acid (0.50 g, 1.1 mmol) was added and stirred at room temperature for 15 hours. Water was added to the reaction mixture, and extracted with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain a colorless oily substance. The obtained colorless oily substance was used as a raw material to obtain the title compound (0.16 g) in the same manner as in Reference Example 23 (pale yellow oily substance).

MS (ESI pos.) M / z: 507 [M + H] ⁺

Reference Example 26: (±)-(5-fluoro-2-iodophenyl) (2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazin-3-yl) methanone

2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.21 g, 1.0 mmol) and 5-fluoro-2-iodobenzoic acid obtained in Reference Example 22 (0.16 g, 0.60 mmol) was used, and the title compound (0.15 g) was obtained by the same method as in Reference Example 25 (pale yellow oil).

MS (ESI pos.) M / z: 511 [M + H] ⁺

Reference Example 27: Ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate

Copper (I) iodide in a DMF (300 mL) solution of ethyl-1H-pyrazole-3-carboxylate (25.0 g, 178.4 mmol) and 2-bromo-5-fluoropyridine (47.1 g, 267.6 mmol) 8.5g, 44.6mmol), rac-trans-N, N'-dimethylcyclohexane-1,2-diamine (28.1mL, 178.4mmol) and Cs ₂ CO ₃ (116.2g, 356.8mmol) were added and 90 ° C It was stirred for 7 hours. After cooling to room temperature, water and EtOAc were added to the reaction mixture, and filtered through Celite (registered trademark). The organic layer was taken out from the filtrate, washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 50g, hexane / EtOAc = 70/30 to 0/100). The obtained solid was stirred and washed in hexane / EtOAc = 4/1, filtered, and the title compound (29.0 g) was obtained (colorless solid).

MS (ESI pos.) M / z: 236 [M + H] ⁺

Reference Example 28: [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol

Hydrogenated diisobutylaluminum in a THF (50 mL) solution of ethyl-1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carboxylate (10.0 g, 42.5 mmol) obtained in Reference Example 27 (1.01 mol / L toluene solution, 105.2 mL, 106.3 mmol) was added under cooling at -78 ° C, and after dropping, the temperature was raised to 0 ° C and stirred for 2 hours. To the reaction mixture, an aqueous solution of sodium potassium tartrate (rocel salt) was added under ice-cooling, and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain the title compound (8.0 g) (colorless solid).

MS (ESI pos.) M / z: 194 [M + H] ⁺

Reference Example 29: 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde

85% Manganese Dioxide in a CHCl ₃ (100 mL) suspension of [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methanol (8.0 g, 34.0 mmol) obtained in Reference Example 28 ( 29.6 g, 0.34 mol) was added and stirred at 60 ° C for 3 hours. The reaction mixture was filtered through Celite (registered trademark), the solid was washed with CHCl ₃ , and the filtrate was concentrated under reduced pressure. The obtained residue was washed with diethyl ether, filtered off to obtain the title compound (5.3 g) (light brown solid).

MS (ESI pos.) M / z: 192 [M + H] ⁺

Reference Example 30: [1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetaldehyde

To a THF (50 mL) solution of methoxymethyltriphenylphosphonium chloride (5.4 g, 15.7 mmol), n-butyllithium (2.6 mol / L hexane solution, 6.3 mL, 16.5 mmol) was added under cooling at -78 ° C, 30 Stir for a minute. The temperature was raised to 0 ° C., and 1- (5-fluoropyridin-2-yl) -1H-pyrazole-3-carbaldehyde (1.5 g, 7.9 mmol) obtained in Reference Example 29 and hexamethyl phosphate triamide (0.5 After adding THF (50 mL) solution of mL) and stirring for 3 hours, the temperature was raised to room temperature and stirred for 15 hours. EtOAc and saturated aqueous sodium chloride solution were added to the reaction mixture under ice bath cooling and stirred, and the organic layer was separated. After drying with MgSO ₄ , the drying agent was filtered off, and the solvent was distilled off under reduced pressure to obtain a brown oily substance. An aqueous hydrochloric acid solution (1.2 mol / L, 10 mL) was added to the obtained brown oily substance, heated to reflux, and stirred for 2 hours. After cooling at room temperature, water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 25 g, hexane / EtOAc = 80/20 to 20/80) to obtain the title compound (1.0 g) (light yellow oily substance).

MS (ESI pos.) M / z: 206 [M + H] ⁺

Reference Example 31: [2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] meta Paddy field

(±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2-) obtained in Reference Example 4 1) Phenyl] Methanone (1.7g, 5.7mmol) in a toluene (29mL) solution of pyridinium paratoluenesulfonic acid (0.14g, 0.57mmol) and (S) -5-allyl-2-oxabicyclo [3.3.0 ] Oct-8-ene (1.0 g, 6.9 mmol) was added and stirred at an oil bath temperature of 70 ° C. Cool to room temperature, add saturated aqueous NaHCO ₃ and extract with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 160 g, hexane / EtOAc = 75/25 to 40/60) to obtain a low-polar compound (0.89 g) in the two types of diastereomer mixtures (colorless solid). Tosylic acid monohydrate (0.075 g, 0.4 mmol) was added to a MeOH (40 mL) solution of the obtained colorless solid diastereomer and stirred at room temperature for 15 hours. Saturated aqueous NaHCO ₃ solution was added to the reaction mixture, followed by extraction with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75/25 to 0/100), (KP-NH 10 g, hexane / EtOAc = 75/25 to 0/100) to give the title compound (0.58 g, 94% ee) (colorless oily substance). The optical purity was analyzed based on the above-described racemic analysis conditions (condition 10, Rt ¹ = 10.2 min, Rt ² = 11.6 min), and compounds with short relative retention times (Rt ¹ = 10.2 min) were obtained in excess.

MS (ESI pos.) M / z: 303 [M + H] ⁺

The title compound can also be synthesized by other methods shown below.

(±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazole-2-) obtained in Reference Example 4 1) Phenyl] Methanone (1.0mg, 0.0033mmol), vinyl acetate (0.05mL), t-butyl methyl ether (1mL) solution in pig pancreas-derived lipase (9.5mg, trade name Lipase from porcine pancreas Type II, manufactured by SIGMA) Was added and stirred at 35 ° C. in a screw vial at 250 rpm for 24 hours with shaking. The reaction solution was filtered with Ekikuro Disc 13CR (manufactured by Nippon Falls). The filtrate was concentrated under reduced pressure, and the obtained residue was subjected to HPLC analysis under the above-described racemic analysis condition 10, and acetic acid {3- [5-methyl-2- (2H-1,2,3-triazole-2- 1) benzoyl] -1,3-oxazinan- ² -yl} methyl (excessive, colorless oily substance with long retention time in 54.5%, 81.2% ee, Rt ¹ = 7.3 min, Rt ² = 8.9 min) The title compound (45.5%,> 99.9% ee, Rt ¹ = 10.2 min, Rt ² = 11.6min in which the shorter retention time is, the more colorless oily substance was) was obtained.

MS (ESI pos.) M / z: 303 [M + H] ⁺

The title compound can also be synthesized by other methods shown below.

Trifluoromethanesulfonic acid copper (II) (0.013g, 0.040mmol) and (R, R) -2,2'-isopropylidenebis (4-phenyl-2-oxazoline) (0.012g, 0.040mmol) (±)-[2- (hydroxymethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2, obtained in Reference Example 4) in THF solution (1.5 mL) 3-triazol-2-yl) phenyl] methanone (0.36g, 1.2mmol), potassium carbonate (0.16g, 1.2mmol), benzoyl chloride (0.069g, 0.59mmol) were added and stirred at room temperature for 3 hours. Water was added to the reaction mixture and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75/25 to 0/100), thereby benzoic acid {3- [5-methyl-2- (2H-1,2,3-triazole) -2-yl) benzoyl] -1,3-oxazinan-2-yl} methyl (0.16 g, 55% ee) was obtained (colorless oil). The optical purity was analyzed based on the above-described racemic analysis conditions (condition 10, Rt ¹ = 6.9 min, Rt ² = 7.9 min), and compounds with a short relative retention time (Rt ¹ = 6.9 min) were obtained in excess. Potassium carbonate (0.010 g, 0.074 mmol) was added to a MeOH solution (0.5 mL) of the obtained colorless oily substance (0.020 g, 0.049 mmol) and stirred at room temperature for 2 hours. Water was added to the reaction mixture and extracted with EtOAc. The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 75/25 to 0/100) to obtain the title compound (0.011 g, 55% ee) (colorless oily substance). The optical purity was analyzed based on the above-described racemic analysis conditions (condition 10, Rt ¹ = 10.2 min, Rt ² = 11.6 min), and compounds with short relative retention times (Rt ¹ = 10.2 min) were obtained in excess.

MS (ESI pos.) M / z: 303 [M + H] ⁺

Reference Example 32: [2- (chloromethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[2- (hydroxymethyl) -1,3-oxazinan-3-yl] obtained in Reference Example 31 [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] Methanone (1.8g, 5.8mmol, 86.3% ee) and TEA (1.2mL, 8.7mmol) CHCl ₃ (30mL) solution was added ice-cooled MsCl (0.54mL, 7.0mmol). It heated up to room temperature and stirred for 3 hours. Water was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and then the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 88/12 to 0/100). EtOAc (10 mL) was added to the obtained residue, and after stirring for 30 minutes under ice bath cooling, the solid was filtered off to obtain the title compound (0.81 g, 84.2% ee) (colorless solid). The optical purity was analyzed based on the above-described racemic analysis conditions (condition 12, Rt ¹ = 7.7 min, Rt ² = 11.9 min), and a compound containing a long relative retention time (Rt2 = 11.9 min) in excess Got

MS (ESI pos.) M / z: 321 [M + H] ⁺

Reference Example 33: Ethyl (2RS, 5SR) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinan- 2-carboxylate

Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazinane obtained in Reference Example 18 Potassium carbonate (7.4 g, 53.8 mmol) was added to an ethanol (60 mL) solution of -2-carboxylate (2.1 g, 6.0 mmol), and stirred at 75 ° C. for 7 hours. After cooling to room temperature, water was added to the reaction mixture, the solvent was concentrated under reduced pressure, and extracted with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 120 g, hexane / EtOAc = 90/10 to 30/70) to give the title compound (0.72 g) (colorless oil).

MS (ESI pos.) M / z: 359 [M + H] ⁺

Reference Example 34: [(2RS, 5SR) -2- (hydroxymethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3- Triazole-2-yl) phenyl] methanone

Ethyl (2RS, 5SR) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 33 Using 2-carboxylate (0.72 g, 2.0 mmol) as a raw material, the title compound (0.59 g) was obtained by the same method as in Reference Example 2 (colorless oily substance).

MS (ESI pos.) M / z: 317 [M + H] ⁺

Reference Example 35: (2RS, 5SR)-[2- (chloromethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-tria) Zol-2-yl) phenyl] methanone

[(2RS, 5SR) -2- (hydroxymethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3) obtained in Reference Example 34 -Triazol-2-yl) phenyl] methanone (0.59 g, 1.9 mmol) as a raw material to obtain the title compound (0.52 g) in the same manner as in Reference Example 32 (colorless oily substance).

MS (ESI pos.) M / z: 335 [M + H] ⁺

Example 1: (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl ) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[2- (hydroxymethyl) -1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl obtained in Reference Example 2 ] To a solution of methanone (1.7 g, 5.9 mmol) and TEA (1.2 mL, 8.8 mmol) in CHCl ₃ (30 mL), under ice-water cooling, MsCl (0.55 mL, 7.1 mmol) was added and stirred for 1 hour. Under ice water cooling, water was added and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO ₄ , and the desiccant was separated by filtration, and then the solvent was distilled off under reduced pressure. The resulting residue was purified by column chromatography (HP-Sil 50 g, hexane / EtOAc = 88/12 to 0/100) to give {3- [5-methyl-2- (2H-1,2,3-triazole-2). -Yl) benzoyl] -1,3-oxazolidin-2-yl} methylmethanesulfonate was obtained (pale yellow oil). 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (1.3g, 8.1mmol), Cs ₂ CO ₃ (4.8g, 14.7mmol) was added to the obtained DMF (30mL) solution of the pale yellow oily substance. , It was stirred for 24 hours at 90 ℃ oil bath temperature. Cool to room temperature, add water, extract with EtOAc, and distill off the solvent under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 150 g, hexane / EtOAc = 88/12 to 0/100) to obtain a racemic mixture (1.2 g) of the title compound (pale yellow oil). The obtained racemic mixture was partitioned using a semi-preparation column based on the above-described racemic analysis conditions (condition 1, Rt ¹ = 3.6 min, Rt ² = 7.0 min), and the relative retention time was short (Rt ¹ = 3.6). Min) The title compound (0.39 g) was obtained (colorless solid).

LCMS retention time 0.90 min.

MS (ESI pos.) M / z: 434 [M + H] ⁺

[α] _D ²⁵ = -71.0 (c = 0.0994, CHCl ₃ )

Examples 2 to 4 were obtained by the same method as in Example 1. Table 2 shows the structural formulas, compound names, LCMS data, and non-linearity of the obtained compounds.

Example 5: (-)-[(2S, 5S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1 , 3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Ethyl (2RS, 5S) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl] -1,3-oxazoli obtained in Reference Example 5 [2- (Hydroxymethyl) -5-methyl-1,3-oxazolidine-3 by the same method as in Reference Example 2, using din-2-carboxylate (0.11 g, 0.33 mmol) as a raw material. -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] diastereomeric mixture of methanone was obtained (colorless oil). [(2S, 5S) -2- (hydroxymethyl) -5-methyl-1,3-oxazolidine by purifying the obtained diastereomeric mixture by thin layer chromatography (1 mm, hexane / EtOAc = 50/50) -3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone was obtained (colorless oil). Obtained [(2S, 5S) -2- (hydroxymethyl) -5-methyl-1,3-oxazolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazole -2-yl) phenyl] methanone (30.2mg, 0.10mmol) and TEA (0.021mL, 0.15mmol) in CHCl ₃ (0.8mL) solution, cooled with ice water, and added MsCl (0.011mL, 0.15mmol) , And stirred for 1 hour. Under ice water cooling, water was added and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.033 g, 0.20 mmol), Cs ₂ CO ₃ (0.065 g, 0.20 mmol) was added to the NMP (0.5 mL) solution of the obtained residue. . It was reacted for 1 hour under microwave irradiation at 120 ° C. After cooling, water was added to extract with CHCl ₃ , passed through an isolute phase separator, and the solvent was distilled off under reduced pressure. The obtained residue was purified by HPLC to obtain the title compound (0.020 g) (colorless oil).

LCMS retention time 0.92 min.

MS (ESI pos.) M / z: 448 [M + H] ⁺

[α] _D ²⁵ = -80.4 (c = 0.0828, CHCl ₃ )

Examples 6 to 10 were obtained by the same method as in Example 5. Table 3 shows the structural formulas, compound names, LCMS data, and non-linearity of the obtained compounds.

Example 11: (±)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl ) [2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

To a solution of CHCl ₃ (72 mL) of 2- [1- (2,2-diethoxyethyl) -1H-pyrazol-3-yl] -5-fluoropyridine (4.0 g, 14.3 mmol) obtained in Reference Example 12 TFA (6.4 mL, 85.9 mmol) was added and stirred at 35 ° C. for 6 hours. TFA (6.4 mL, 85.9 mmol) was added and stirred at 35 ° C. for 3 hours. After cooling to room temperature, NaHCO ₃ aqueous solution was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with saturated aqueous sodium chloride solution, dried over MgSO _4, and the drying agent was filtered off. The solvent was distilled off under reduced pressure to obtain [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde (colorless oily substance). To a solution of [3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] acetaldehyde in CHCl ₃ (36 mL), activated Molecular Sieve 4A (29 g), 2-aminoethanol ( 1.1 mL, 14.3 mmol) was added and stirred at room temperature for 48 hours. After filtration separation of the Molecular Sieve 4A by Celite (registered trademark) filtration, the solvent was distilled off under reduced pressure to obtain a colorless oily substance. To a DMF (0.4 mL) solution of the obtained colorless oil (0.10 g, 0.40 mmol) and 2- (2H-1,2,3-triazol-2-yl) benzoic acid (76 mg, 0.40 mmol), DIPEA (0.21 mL) , 1.2mmol) and HATU (0.16g, 0.48mmol) were added and stirred at room temperature for 48 hours. The reaction mixture was purified by HPLC to give the title compound (40.8 mg) (colorless solid).

LCMS retention time 0.83 min.

MS (ESI pos.) M / z: 420 [M + H] ⁺

Examples 12 to 38 were obtained by the same method as in Example 11. Examples 26 to 32 and Examples 34 to 38 were optically divided by the same method as in Example 1. Table 4 shows the structural formula, compound name, LCMS data, and non-linearity of the obtained compound.

Example 39: [(2S, 4S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxa Last-3-day} [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[(2S, 4S) -2- (hydroxymethyl) -4-methyl-1,3-oxazinan-3-yl] obtained in Reference Example 17 [5-methyl-2- (2H-1,2,3) -Triazol-2-yl) phenyl] 5-fluoro-2- (1H-pyrazol-4-yl) pyridine obtained in Reference Example 11 in a toluene (1 mL) solution of methanone (0.070 g, 0.22 mmol) (0.040 g, 0.24 mmol) and cyanomethylene tributylphosphorane (0.087 mL, 0.33 mmol) were added and stirred at 100 ° C. for 3 hours. The solvent was distilled off under reduced pressure, and the obtained residue was subjected to column chromatography (KP-NH 12 g, hexane / EtOAc = 80/20 to 0/100) (HP-Sil 10 g, hexane / EtOAc = 80/20 to 0/100). Purified by and the title compound (0.11 g) was obtained (colorless oily substance).

LCMS retention time 0.96 min.

MS (ESI pos.) M / z: 462 [M + H] ⁺

Example 40: (-)-[(2S *, 5S *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Ethyl (2RS, 5RS) -5-methyl-3- [5-methyl-2- (2H-1,2,3-triazol-2-yl) benzoyl) -1,3-oxazinane obtained in Reference Example 18 Using -2-carboxylate (0.13 g, 0.36 mmol) as a raw material, by the same method as in Reference Example 2, [(2RS, 5RS) -2- (hydroxymethyl) -5-methyl-1,3- Oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone (0.098 g) was obtained (colorless oily substance). The obtained colorless oily substance (0.098g, 0.31mmol), 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.056g, 0.34mmol) obtained in Reference Example 11 as a raw material, and Example 39 and A racemic mixture (0.11 g) of the title compound was obtained by the same method. The obtained racemic mixture was partitioned using a semi-preparation column based on the above-described racemic analysis conditions (condition 7, Rt ¹ = 4.3 min, Rt ² = 4.8 min), and the relative retention time was short (Rt ¹ = 4.3). Min) The title compound (0.044 g) was obtained (colorless oily substance).

LCMS retention time 0.94 min.

MS (ESI pos.) M / z: 462 [M + H] ⁺

[α] _D ²³ = -44.1 (c = 0.0704, CHCl ₃ )

Example 41: (-)-[2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone

(±)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) obtained in Reference Example 23 (2- Pd (PPh ₃ ) ₄ (0.044 g) in a toluene (4 mL) solution of iodo-5-methylphenyl) methanone (0.19 g, 0.38 mmol) and 2- (tributylstannanyl) pyrimidine (0.15 mL, 0.46 mmol) , 0.04 mmol), copper iodide (0.0070 g, 0.040 mmol), and cesium fluoride (0.12 g, 0.76 mmol) were added, and the mixture was heated and stirred at 130 ° C. for 0.5 hour under microwave irradiation. An aqueous potassium fluoride solution was added to the reaction mixture, and extracted with CHCl ₃ . The organic layer was washed with aqueous potassium fluoride solution, water and saturated aqueous sodium chloride solution. The organic layer was dried over Na ₂ SO ₄ , and the desiccant was separated by filtration, and then concentrated under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 10 g, hexane / EtOAc = 80/20 to 0/100) (KP-NH 12 g, hexane / EtOAc = 80/20 to 0/100), and the title compound was A semi-mixture (0.099 g) was obtained (colorless oily substance). The obtained racemic mixture was divided using a semi-preparation column based on the above-described racemic analysis conditions (condition 4, Rt ¹ = 3.9 min, Rt ² = 13.7 min), and the relative retention time was short (Rt ¹ = 3.9). Min) The title compound (0.036 g) was obtained (colorless oily substance).

LCMS retention time 1.0 min.

MS (ESI pos.) M / z: 458 [M + H] ⁺

[α] _D ²³ = -34.1 (c = 0.0914, CHCl ₃ )

Examples 42-44 were obtained by the method similar to Example 41. Table 42 shows the structural formulas, compound names, LCMS data, and specificity of Examples 42 to 44.

Example 45: (-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methyl} -1,3-oxazolidin-3-yl ] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

[1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] acetaldehyde (0.80 g, 3.9 mmol) obtained in Reference Example 30 was used, and the same method as in Example 11 was used. This gave a racemic mixture (0.063 g) (light yellow solid). The obtained racemic mixture (0.050 g, 0.12 mmol) was partitioned using a semi-preparation column based on the racemic analysis conditions described above (condition 9, Rt ¹ = 4.6 min, Rt ² = 13.8 min), and relative retention time This short (Rt ¹ = 4.6 min) gave the title compound (0.017 g) (colorless solid).

LCMS retention time 1.0 min.

MS (ESI pos.) M / z: 434 [M + H] ⁺

[α] _D ²³ = -104.0 (c = 0.0566, CHCl ₃ )

Example 46: (-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazolidin-3-yl ] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.30 g, 1.5 mmol) obtained in Reference Example 22 was used as a raw material in the same manner as in Reference Example 25. This gave a racemic mixture (0.039 g) of the title compound (colorless oily substance). The obtained racemic mixture was divided using a semi-preparation column based on the above-described racemic analysis conditions (condition 2, Rt ¹ = 16.3 min, Rt ² = 19.2 min), and the relative retention time was short (Rt ¹ = 16.3). Min) The title compound (0.0076 g) was obtained (colorless solid).

LCMS retention time 0.97 min.

MS (ESI pos.) M / z: 434 [M + H] ⁺

[α] _D ²³ = -80.9 (c = 0.0478, CHCl ₃ )

Example 47: (-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

2- [1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] ethanol (0.30 g, 1.5 mmol) obtained in Reference Example 22 was used as a raw material in the same manner as in Reference Example 25. This gave a racemic mixture (0.19 g) of the title compound (colorless solid). The obtained racemic mixture (0.20 g, 0.45 mmol) was partitioned using a semi-preparation column based on the above-described racemic analysis conditions (condition 11, Rt ¹ = 9.9 min, Rt ² = 11.5 min), and relative retention time This short (Rt ¹ = 9.9 min) gave the title compound (0.0095 g) (colorless solid).

LCMS retention time 0.97 min.

MS (ESI pos.) M / z: 448 [M + H] ⁺

[α] _D ²³ = -21.4 (c = 0.109, CHCl ₃ )

Example 48: (-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

Sodium hydride (55%, 0.12 g, 2.7 mmol) was added to a DMF (9 mL) solution of 5-fluoro-2- (1H-pyrazol-3-yl) pyridine (0.36 g, 2.2 mmol) obtained in Reference Example 10. It was added and stirred at room temperature for 30 minutes. [2- (chloromethyl) -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] meta obtained in Reference Example 32 DMF (3 mL) solution of paddy (0.79 g, 2.5 mmol, 84.2% ee) was added dropwise. The mixture was stirred at 90 ° C for 1 hour. After cooling to room temperature, water was added to the reaction mixture, and extracted with EtOAc. The organic layer was washed with water and saturated aqueous sodium chloride solution, dried over Na ₂ SO _4, and the drying agent was filtered off, and the solvent was distilled off under reduced pressure. The obtained residue was purified by column chromatography (HP-Sil 40g, hexane / EtOAc = 70/30 to 0/100). EtOH (10 mL) was added, stirred for 1 hour under ice bath cooling, filtered off to obtain the title compound (0.60 g,> 99.9% ee, having stereochemistry similar to Example 3) (colorless solid). The optical purity was analyzed based on the above-described racemic analysis conditions (condition 9, Rt ¹ = 4.3 min, Rt ² = 6.7 min), and compounds with a short relative retention time (Rt ¹ = 4.3 min) were obtained in excess.

LCMS retention time 0.90 min.

MS (ESI pos.) M / z: 448 [M + H] ⁺

Example 49: (-)-[(2S *, 5R *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl -1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone

(2RS, 5SR)-[2- (chloromethyl) -5-methyl-1,3-oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-) obtained in Reference Example 35 Triazole-2-yl) phenyl] methanone (0.52g, 1.5mmol), 5-fluoro-2- (1H-pyrazol-4-yl) pyridine (0.23g, 1.4mmol) obtained in Reference Example 11 The title compound (0.44 g) was obtained by the same method as in Example 48. The obtained racemic mixture (0.070 g) was partitioned using a semi-preparation column based on the above-described racemic analysis conditions (condition 13, Rt ¹ = 6.6 min, Rt ² = 12.4 min), and the relative holding time was short ( Rt ¹ = 6.6 min) The title compound (0.030 g) was obtained (colorless oily substance).

LCMS retention time 0.95 min.

MS (ESI pos.) M / z: 462 [M + H] ⁺

[α] _D ²⁵ = -14.1 (c = 0.0870, CHCl ₃ )

Test example (measurement of orexin antagonistic activity)

The antagonistic activity of the test compound on the human orexin type 1 receptor (hOX1R), orexin type 2 receptor (hOX2R) was described in the method described in Toshikatsu Okumura et al., Biochemical and Biophysical Research Communications 280, 976-981, 2001. I changed and did it. Chinese hamster ovary (CHO) cells forcedly expressing hOX1R and hOX2R were seeded to 20,000 in each well of a 96-well black clear bottom plate (Nunc). , Cultured in Ham's F-12 medium (abnormal invitrogen) containing 0.1 mM MEM non-essential amino acid, 0.5 mg / ml G418, 10% fetal calf serum at 37 ° C. for 5 hours under 5% CO 2 conditions. After removing the medium, an analytical buffer solution containing 0.5 μM Fluo-3AM ester (dojin) (25 mM HEPES (dojin), Hanks' balanced salt solution (Invitrogen), 0.1% bovine serum albumin, 100 μL of 2.5 mM probenecid, 200 μg / ml Amaranth (abnormal Sigma-Aldrich), pH7.4) was added and incubated at 37 ° C., 5% CO 2 for 60 minutes. After removing the analytical buffer containing Fluo-3AM ester, the test compound was dissolved with dimethyl sulfoxide to be 10 mM, diluted with the analytical buffer, and 150 μL was added, followed by incubation for 30 minutes.

Peptide substituted with the amino acid of human orexin-A, a ligand (Pyr-Pro-Leu-Pro-Asp-Ala-Cys-Arg-Gln-Lys-Thr-Ala-Ser-Cys-Arg-Leu-Tyr-Glu- Leu-Leu-His-Gly-Ala-Gly-Asn-His-Ala-Ala-Gly-Ile-Leu-Thr-Leu-NH2; Peptide Lab) analyzed to a final concentration of 300pM for hOX1R and 3mM for hOX2R The reaction was initiated by dilution with a solution buffer and 50 μL of this ligand solution was added. The reaction was measured using a functional drug screening system (FDSS; manufactured by Hamamatsu Photonics) for 3 minutes per second for each well, and the maximum fluorescence was antagonized as an index of intracellular Ca2 + concentration. Activity was determined. When the antagonistic activity of the test compound was calculated as 100% of the fluorescence value of the well added with only the dilution buffer, and the fluorescence value of the well with no buffer containing the ligand and the compound was calculated as 0%, and various concentrations of the test compound were added. The 50% inhibitory concentration (IC ₅₀ value) was determined from the fluorescence value of.

Table ₅₀ shows the IC ₅₀ values of the compounds of the present invention.

It has been shown that the compounds of the present invention have OX receptor antagonism. Accordingly, the compound of the present invention or a pharmaceutically acceptable salt thereof is a disease controlled by OX receptor antagonism, such as sleep disorder, depression, anxiety disorder, panic disorder, ataxia, drug dependence, Alzheimer's disease, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, hypertension, etc. can be used as a treatment or prevention drug.

Claims (9)

A compound represented by the following formula (IA), or a pharmaceutically acceptable salt thereof.

(In the formula,
X ¹ and X ² represent the same or different nitrogen atom or formula CH,
Y represents the structure of any one of the following formula group (a),

n represents 1 or 2,
R ¹ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group,
R ² represents a triazolyl group, pyridyl group or pyrimidinyl group,
R ³ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group (wherein said C _{1 -6} alkyl group may be substituted with 1 to 3 halogen atoms),
R ⁴ represents a hydrogen atom or a C _{1 -6} alkyl group) According to claim 1, in the formula (IA),
R ² is a triazolyl group or pyrimidinyl group,
A compound wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof. According to claim 1, in the formula (IA),
A compound wherein n is 2, or a pharmaceutically acceptable salt thereof. A compound represented by the following formula (I), or a pharmaceutically acceptable salt thereof.

(In the formula,
X ¹ and X ² represent the same or different nitrogen atom or formula CH,
Y ¹ and Y ² are nitrogen atoms on one side and CH on the other side,
n represents 1 or 2,
R ¹ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group,
R ² represents a triazolyl group, pyridyl group or pyrimidinyl group,
R ³ is a hydrogen atom, a halogen atom or a C _{1 -6} alkyl group (wherein said C _{1 -6} alkyl group may be substituted with 1 to 3 halogen atoms),
R ⁴ represents a hydrogen atom or a C _{1 -6} alkyl group) According to claim 4, in the formula (I),
R ² is a triazolyl group or pyrimidinyl group,
A compound wherein R ³ is a halogen atom, or a pharmaceutically acceptable salt thereof. According to claim 4, in the formula (I),
A compound wherein n is 2, or a pharmaceutically acceptable salt thereof. Any one or two or more mixtures selected from the following group of compounds described in claim 1 and pharmaceutically acceptable salts thereof.
(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S, 5S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S, 5R) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
[(2S, 4R) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazolidine-3 -Yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S, 4S) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxa Zolidin-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(±) -2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl] [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,
(±)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5- Fluoro-2- (pyrimidin-2-yl) phenyl] methanone,
(±)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(±)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [5-methyl-2- (Pyrimidin-2-yl) phenyl] methanone,
(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazolidin-3-yl) [6-methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( 2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( Pyrimidin-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-fluoro Ro-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-(2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,
(-)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( 2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,
(-)-(2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl) [6-methyl-3- ( Pyrimidin-2-yl) pyridin-2-yl] methanone,
(-)-[2-{[3- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro Ro-2- (pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( 2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[5- (5-fluoropyridin-2-yl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl ] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[5- (4-fluorophenyl) -1,2,4-oxadiazol-3-yl] methyl} -1,3-oxazinan-3-yl] [6- Methyl-3- (2H-1,2,3-triazol-2-yl) pyridin-2-yl] methanone,
[(2S, 4S) -2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -4-methyl-1,3-oxazinan-3- Il} [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S *, 5S *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3 -Oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[3- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone,
(±)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[4- (4-fluorophenyl) -1H-pyrazol-1-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl-2- ( Pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-fluoro Ro-2- (pyrimidin-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-3-yl] methyl} -1,3-oxazolidin-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazolidin-3-yl] [5- Methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[2-{[1- (5-fluoropyridin-2-yl) -1H-pyrazol-4-yl] methyl} -1,3-oxazinan-3-yl] [5-methyl -2- (2H-1,2,3-triazol-2-yl) phenyl] methanone,
(-)-[(2S *, 5R *)-2-{[4- (5-fluoropyridin-2-yl) -1H-pyrazol-1-yl] methyl} -5-methyl-1,3 -Oxazinan-3-yl] [5-methyl-2- (2H-1,2,3-triazol-2-yl) phenyl] methanone. Sleep disorders, depression, anxiety disorders, panic disorders, ataxia (schizophrenia), drug dependence, Alzheimer's, containing the compound according to any one of claims 1 to 7, or a pharmaceutically acceptable salt thereof as an active ingredient. Diseases, Parkinson's disease, Huntington's chorea, eating disorders, headache, migraine, pain, digestive diseases, epilepsy, inflammation, immune-related diseases, endocrine-related diseases, or drugs for the treatment of hypertension. delete